This program will focus on mechanisms of mediation and regulation of compartmental immunity in lungs and skin by substance P (SP) and vasoactive intestinal peptide (VIP) released from regional peptidergic nerves. Anti- receptor (R) antibodies and nucleic acid probes, specific for the recently cloned SPR and high-and low-affinity VIPRs, will be used to localize each R and R MRNA in respiratory tissues and skin, analyze the molecular bases for R binding specificity and desensitization, and develop genetic, immunochemical and pharmacological methods for inhibiting the Rs (Project 1). The finding of SP and VIP in pulmonary secretions after intratracheal antigen challenge of immunized mice and the later appearance in the lungs of lymphocytes bearing SPRs and VIPRs suggests involvement of SP and VIP in regional immune responses. The roles of SP and VIP in attraction and function of pulmonary lymphocytes will be delineated directly by introducing Rs genetically and blocking effective R expression with antisense techniques and anti-R antibodies (Project 2). The capacity of mast cells from human skin, but not lung, and of keratinocytes to respond specifically to SP and VIP will be examined in terms of receptor-dependent and -independent mechanisms, including analyses of direct binding of SP and VIP to quanine nucleotide-binding (G) proteins (Project 3). Female sex hormones control many aspects of lung function and contribute to alterations in asthma during pregnancy. The possible adverse effects of premenstrual and menopausal hormone changes, and oral contraceptives on asthma severity, suggested by the results of a recent mail survey, will be the subject of a prospective study designed to assess rigorously the significance of effects of female sex hormones on the course of asthma, an to demonstrate possible benefits of maintenance estrogens.